Among the high-quality abstract presentations at the 2024 San Antonio Breast Cancer Symposium (SABCS), a few always stand out as particularly meritorious. Each year, The ASCO Post asks our Deputy Editor, breast cancer specialist Jame Abraham, MD, FACP, to give us his picks. Dr. Abraham is Chairman of the Department of Hematology and Medical Oncology at Cleveland Clinic and Professor of Medicine at Lerner College of Medicine.
Jame Abraham, MD, FACP
AFT-38 PATINA Trial: Palbociclib as Maintenance Therapy
Late-breaking results of the phase III AFT-38 PATINA trial showed the value of adding the CDK4/6 inhibitor palbociclib to maintenance therapy in patients with hormone receptor–positive, HER2-positive metastatic breast cancer.1 The combination yielded a statistically significant and clinically meaningful 15-month improvement in progression-free survival. Median progression-free survival was 44 months with palbociclib plus endocrine therapy and the monoclonal antibody trastuzumab or trastuzumab plus the monoclonal antibody pertuzumab vs 29 months with anti-HER2 therapy plus endocrine therapy alone (hazard ratio [HR] = 0.74; P = .0074).
PATINA enrolled 518 patients with hormone receptor–positive, HER2-positive metastatic breast cancer and no prior therapy in the advanced setting. After induction with anti-HER2 therapy and chemotherapy, patients without disease progression were randomly assigned to receive anti-HER2 therapy and endocrine therapy (fulvestrant or an aromatase inhibitor) with or without palbociclib. Almost all patients received dual anti-HER2 therapy and an aromatase inhibitor.
At a median follow-up of 53 months, the addition of palbociclib significantly improved progression-free survival by 26% compared with the control arm; benefit was seen in all stratification subsets. The objective response rate was 29.2% in the palbociclib arm vs 22.2% in the control arm, and the clinical benefit rate was 89% vs 81.3%, respectively. Though immature, median overall survival was not reached in the palbociclib arm and was 77 months in the control arm. The 5-year survival rate was 74.3% vs 69.8%, respectively.
Dr. Abraham: PATINA is a very important study. It is the first phase III trial to show the addition of the CDK4/6 inhibitor palbociclib to anti-HER2 and endocrine therapy is beneficial as first-line maintenance therapy in hormone receptor–positive, HER2-positive metastatic breast cancer. The strong scientific rationale—the potential synergy of these agents in combination—is reinforced by PATINA’s findings. The median progression-free survival of 4 years extends the time to chemotherapy by almost 1.5 years. It shows the durability and tolerability of this regimen and suggests that palbociclib may be overcoming resistance to endocrine and anti-HER2 therapy. The data support the potential of this maintenance approach to slow disease progression over the long term without impeding quality of life (as chemotherapy does), which is especially relevant in this more or less chronic disease population.
I think this is a potentially practice-changing study, but there are some caveats. A number of trials are looking at the role of other agents in the first-line setting, such as the antibody-drug conjugate fam-trastuzumab deruxtecan-mxki (T-DXd), which is being compared with the combination of docetaxel, trastuzumab, and pertuzumab. HER-2-targeted tyrosine kinase inhibitors such as tucatinib are also being evaluated, especially for maintenance. We will need to see how these agents all play out, but for now, the findings can be clinically applied in this population.
COMET: Some Patients With DCIS May Avoid Surgery
In the COMET trial, active monitoring in patients with low-risk ductal carcinoma in situ (DCIS) proved to be noninferior to guideline-concordant management (ie, surgery with or without radiation therapy).2 After 2 years of follow-up, 19 of 473 patients assigned to active monitoring and 27 of 484 patients in the guideline-concordant care arm were diagnosed with invasive ipsilateral breast cancer, yielding rates of 4.2% and 5.9%, respectively, and meeting the standard for noninferiority. No significant differences were seen in subgroups.
COMET enrolled nearly 1,000 patients (aged 40 or older) with a new diagnosis of low-risk DCIS (ie, grade 1 or 2, hormone receptor–positive, HER2-negative disease with no evidence of invasive breast cancer). Active monitoring consisted of yearly bilateral mammograms interspersed with mammograms every 6 months for the DCIS-affected breast for 5 years. Surgery was recommended upon signs of progression to invasive cancer. Guideline-concordant management entailed surgery with or without radiation therapy. Radiotherapy was delivered to 7.4% of the guideline-concordant group and 26.6% of the monitored group. Lumpectomy was performed in 13.2% and 48.2%, respectively, and mastectomy was performed in 3.7% and 5.5%, respectively. All patients could have endocrine therapy if desired.
Almost half the patients assigned to guideline-concordant care declined surgery, so the investigators performed a separate per-protocol analysis of 673 patients who adhered to their assigned treatment. In that analysis, the 2-year rate of invasive ipsilateral breast cancer was 3.1% with active monitoring and 8.7% with guideline-concordant care, for an absolute difference of 5.6% favoring active monitoring. Among patients who received endocrine therapy, cancer developed in 3.2% of the monitored group compared with 7.2% of the guideline-concordant group. Health-related quality of life, anxiety, depression, worries about DCIS, and symptom trajectories were comparable in both arms of the study over 2 years of follow-up.
Dr. Abraham: For almost all patients with newly diagnosed DCIS, the standard treatment is surgery, often combined with radiation in patients who had lumpectomy and endocrine therapy for estrogen receptor–positive DCIS. But since nearly 80% of DCIS do not progress to invasive cancer, many such patients are overtreated. COMET is the first large randomized clinical trial in the United States to evaluate different management strategies for DCIS, including omission of surgery. The finding—that active monitoring does not compromise outcomes—is reassuring and serves as a first step in helping physicians and patients make informed decisions. It is important to realize that the results do not apply to all patients with DCIS—only to those meeting the low-risk criteria used to select patients for the trial. The results suggest that in the short term, active monitoring is a reasonable approach to managing low-risk DCIS; however, in my opinion, they do not change the practice recommendations until proven durable in longer-term analyses.
EMBER: Imlunestrant Improves Progression-Free Survival
In the EMBER-3 trial, the next-generation oral selective estrogen receptor degrader (SERD) imlunestrant significantly reduced the risk of disease progression or death over standard endocrine therapy in patients with estrogen receptor–positive, HER2-negative advanced breast cancer.3,4 As monotherapy, compared mostly with fulvestrant, imlunestrant reduced this risk by 38% in patients with ESR1 mutations—but not in the overall study population. The combination regimen of imlunestrant plus the CDK4/6 inhibitor abemaciclib, however, improved progression-free survival by 43% vs imlunestrant alone in all patients (regardless of ESR1 mutation status).
The 874 patients were randomly assigned to one of three groups:
- Group A: imlunestrant at 400 mg/d
- Group B: standard-of-care endocrine therapy (fulvestrant or exemestane)
- Group C: imlunestrant plus abemaciclib (vs imlunestrant alone).
Progression-free survival was compared between groups A and B in patients with ESR1 mutations and between groups A and B in all patients. Group C analyzed imlunestrant only if one of the imlunestrant vs standard-of-care endocrine therapy endpoints was significant. Median progression-free survival outcomes follow:
- Imlunestrant monotherapy vs standard endocrine therapy in ESR1-mutant: 5.5 vs 3.8 months (HR = 0.62; P < .001)
- Imlunestrant monotherapy vs standard endocrine therapy in the overall population (all-comers): 5.6 vs 5.5 months (HR = 0.87; P = .12)
- Imlunestrant plus abemaciclib vs standard endocrine therapy in ESR1-mutant disease: 11.1 vs 5.5 months (HR = 0.53)
- Imlunestrant plus abemaciclib vs standard endocrine therapy in the overall population (all-comers): 9.4 vs 5.5 months (HR = 0.57; P < .001).
The benefit of the combination of imlunestrant plus abemaclib was observed regardless of the presence of ESR1 mutations. For both the monotherapy and combination-therapy analyses, consistent benefits were observed regardless of the presence or absence of visceral metastases, prior CDK4/6 inhibitor treatment, or PI3K pathway mutation status. The safety data raised no concerns.
Dr. Abraham: Combining a SERD with a CDK4/6 inhibitor can be beneficial when metastatic breast cancer progresses on an aromatase inhibitor regimen, but the most commonly used SERD, fulvestrant, requires monthly injections, and the bioavailability of the fulvestrant injection may not be predictable. The novel orally available SERDs are expected to improve the patient experience, achieve higher drug levels, and be more effective against ESR1 mutations. EMBER showed a robust benefit for imlunestrant, especially when given with abemaciclib, and this was consistent across clinically relevant subgroups: patients who had received a CDK4/6 inhibitor previously, had tumors with or without an ESR1 mutation, or had a PI3K mutation. I believe the data for this highly effective oral SERD are practice-changing.
INSEMA: Omission of SLNB in Low-Risk Early Breast Cancer
The omission of axillary sentinel lymph node biopsy (SLNB) does not compromise survival in women with low-risk, early-stage invasive breast cancer undergoing breast-conserving surgery, according to the INSEMA trial.5 The study enrolled 5,502 patients with clinically node-negative stage T1 (mostly) or T2 (tumor size ≤ 5 cm) who underwent breast-conserving surgery and full breast irradiation. Almost all patients had hormone receptor–positive, HER2-negeative disease.
In the per-protocol population, for the 3,896 who underwent SLNB and the 962 who did not, the 5-year invasive disease–free survival rates were both approximately 92%. The 5-year overall survival rates were 96.9% with SLNB and 98.2% without SLNB, which were statistically comparable. Distant relapse occurred in less than 3% per group. As expected, the rate of axillary recurrence was slightly higher without SLNB than with it (1.0% vs 0.3%), but there were few events. The omission of SLNB significantly reduced lymphedema, arm mobility restrictions, and pain with arm or shoulder movement.
Dr. Abraham: The concept of eliminating SLNB is supported by long-standing data that began with the Danish Breast Cancer Cooperative Group in the 1980s. Their study showed that regardless of the number of nodes removed, the survival benefit was unchanged. The INSEMA study adds to a growing body of data showing SLNB omission does not compromise oncologic outcomes. It is still a necessary staging modality for many patients; its omission is essentially appropriate only for tumors ≤ 2 cm, because larger tumors carry higher rates of sentinel node positivity and have implications for adjuvant therapy. These findings are probably not yet practice-changing, but they will contribute to a trend that is moving in that direction for patients with a limited burden of axillary involvement.
PADMA: Endocrine Therapy Plus Palbociclib in High-Risk Metastatic Disease
The primary analysis of the phase IV PADMA trial showed that the combination of palbociclib with endocrine therapy significantly outperformed standard chemotherapy in 130 patients with high-risk, hormone receptor–positive, HER2-negative metastatic breast cancer.6 PADMA directly compared the efficacy of two treatment approaches: a combination of the CDK4/6 inhibitor palbociclib plus endocrine therapy vs standard single-agent chemotherapy with or without maintenance endocrine therapy.
The primary endpoint, time to treatment failure, was significantly longer with the combination: 17.2 months vs 6.1 months (hazard ratio [HR] = 0.46; P < .001). Median progression-free survival was 18.7 months vs 7.8 months (HR = 0.45; P < .001), and a favorable trend was shown for overall survival, with medians of 46.1 months vs 36.8 months.
Dr. Abraham: PADMA investigated whether an endocrine-based treatment with palbociclib is superior to chemotherapy of physician’s choice as first-line treatment in patients with hormone receptor–positive, HER2-negative, high-risk (ie, have an indication for chemotherapy) metastatic breast cancer. Although international guidelines have recommended this approach for several years, because of limited prospective data when PADMA was initiated, many patients at the time were still receiving chemotherapy.
The results of PADMA certainly leave no doubt that chemotherapy is of no consequential benefit in this population. For three endpoints of time to treatment failure, progression-free survival, and overall survival, approximately 10 months was gained with the use of palbobiclib and endocrine therapy—a highly significant and certainly clinically meaningful difference observed with an oral therapy that also has the advantage of better tolerability than chemotherapy. This combination is now the dominant standard of care, and any questions about this approach can be put to rest! Soon we can anticipate adding a third drug, possibly a targeted agent, to this doublet for even greater effect.
ZEST: Use of ctDNA to Predict Recurrence
The ZEST clinical trial was designed to evaluate the benefit of the PARP inhibitor niraparib in preventing breast cancer recurrence in patients with circulating tumor DNA (ctDNA), though it failed to accrue enough patients with ctDNA-positive disease to reach a conclusion.7 The findings, however, provided some insights into the optimal use of ctDNA in breast cancer management.
The study enrolled 1,901 patients into the ctDNA surveillance study that used serial ctDNA to monitor for measurable residual disease (MRD). The patients had stage I to III triple-negative or BRCA-mutated, hormone receptor–positive breast cancer and had completed their recommended treatment (or were continuing endocrine therapy). A total of 147 patients had detectable ctDNA, almost 60% of whom had detectable levels within 6 months of completing treatment, as did a sizable fraction within 3 months—reflecting the aggressive nature of this subtype. Of the 147 patients, 98 had detectable ctDNA on their first test, and more than half of this group had recurrence detectable by imaging. Of the 48 patients who had detectable ctDNA on subsequent tests, 21 (44%) had recurrence that was detectable by imaging at the time of the first ctDNA-positive test. For various reasons, 40 patients were randomly assigned to niraparib or placebo, with the aim of testing this intervention in those with ctDNA-positive disease. The small population prevented an adequate interpretation of any differences, though a nonsignificant positive trend in progression-free survival was observed with niraparib.
Dr. Abraham: As we all know, about 20% to 30% of early breast cancers will relapse, and we currently do not have a good test to predict who those patients will be. If we are going to optimize our adjuvant therapies, we need markers that will go beyond the current “probabilistic” markers.
Now, we have ctDNA, which has been strongly associated with recurrence and has the potential to identify not only patients at risk but those already with micrometastatic disease. These tests have been used in many other tumor types but have not been validated in breast cancer in terms of their ability to improve long-term outcomes. The randomized ZEST trial tested whether MRD detection after treatment could guide the use of niraparib to improve survival. Unfortunately, it was terminated early, largely because of entry criteria that were too broad, the inclusion of too many low-risk (and therefore ctDNA-negative) patients, and the occurrence of metastatic disease in many patients at the time of ctDNA detection.
We saw that in these patients with triple-negative breast cancer, ctDNA positivity occurred most frequently within the first 6 months from the end of treatment, which is consistent with early recurrence in this subtype. The high rate of radiographic recurrence at the time of ctDNA positivity provides support for starting ctDNA testing earlier in the disease trajectory.
Although ZEST failed to answer its main question, it did provide some insights into the optimal use of ctDNA in breast cancer management based on trial designs that might incorporate these changes:
- Start testing for ctDNA during treatment rather than at treatment completion.
- Include patients with high-risk disease, which may produce more patients with positive ctDNA tests who would therefore be eligible for intervention. An example is the patient with stage IIb or III disease who lacks a pathologic complete response to neoadjuvant therapy.
- Test for ctDNA periodically throughout neoadjuvant therapy, not after it, to help identify patients who remain ctDNA-positive after neoadjuvant therapy. This is particularly relevant for triple-negative breast cancers, which can relapse rapidly if the cancer is not cleared with neoadjuvant treatment.
Is ctDNA ready for clinical use? No. We should not be using this test outside a clinical trial. Eventually, we will have more data about the optimal test, patient, disease setting, diagnostics, and interventions. I understand our patients are anxious to have reassuring information, but we are not yet ready to use these tests for that purpose. The ongoing clinical trial NSABP B 64 (EXActDNA-003) is an important study looking at the role of ctDNA in this setting.
EUROPA: Adjuvant Radiotherapy vs Endocrine Treatment in Older Patients
The phase III EUROPA trial evaluated postoperative radiotherapy vs adjuvant endocrine therapy in older patients with stage I luminal-like breast cancer.8 The study concluded that health-related quality of life was better and treatment-related adverse effects were fewer with radiation therapy; they were equivalent in terms of recurrence risk.
The study randomly assigned 730 patients to receive adjuvant radiation therapy alone or adjuvant endocrine therapy alone; 207 patients with 24 months of follow-up were included in the current analysis. Patients were aged 70 or older; had stage I, luminal A-like breast cancer; and had undergone breast-conserving surgery. Health-related quality of life was assessed by the Global Health Status after 2 years of treatment, and ipsilateral recurrence was calculated at 5 years. The radiotherapy group received either whole- or partial-breast irradiation, whereas the alternate group received aromatase inhibitors or tamoxifen.
At 24 months, median changes from baseline in health-related quality of life were –1.1 with radiotherapy vs –10.0 with endocrine therapy. Adjusted for age and Geriatric 8 score, these changes were –3.40 (P = .13) and –9.79 (P < .0001). Additionally, the radiation therapy group showed better outcomes in terms of physical, role, emotional, cognitive, and social functioning. On the symptoms scale, the radiation group also had more favorable outcomes for most symptoms, including fatigue, nausea and vomiting, pain, dyspnea, insomnia, and appetite loss. With endocrine therapy, on the other hand, several symptoms, such as skin mucositis, significantly worsened. In the interim analysis at 24 months, there had been no ipsilateral recurrences, locoregional relapses, or breast cancer–related deaths in either group.
Dr. Abraham: As breast cancer outcomes continue to improve, we are focusing more on de-escalation strategies to avoid overtreatment and to embrace the patient-centered experience—particularly when there are several effective options with different toxicities. Studies have aimed to show that radiation doses can be reduced, or omitted entirely, in subgroups without affecting oncologic outcomes, but in these studies, the endocrine therapy is continued. Since patients often decide to stop endocrine therapy because of side effects, many are then left without any adjuvant therapy. Now, with shorter-course, ultra-hypofractionated radiotherapy being used increasingly, radiotherapy has become less burdensome. It stands to reason, then, there are patients who would prefer just five fractions of radiotherapy over 5 years of endocrine therapy. EUROPA was designed with these patients in mind and compared the two approaches individually in terms of quality of life and recurrence risk.
The difference was rather clear. The Global Health Status score diminished greatly with endocrine therapy and not with radiotherapy. This effect occurs early on and persists over time. The endocrine therapy group also experienced more side effects, most notably joint pain. EUROPA shows us that radiotherapy is better tolerated in many older patients, without compromising oncologic outcomes, at least at the 24-month mark. In patients who met the inclusion criteria for EUROPA, radiotherapy appears to be a solid alternative to single-agent endocrine therapy, and we should discuss the results with our older patients. Of course, further data on disease control outcomes from the final analysis are needed for confidence.
DISCLOSURE: Dr. Abraham has received research funding from Daiichi Sankyo/AstraZeneca, Pfizer, and Seattle Genetics and served as a consultant to ThinkBio.Ai.
REFERENCES
- Metzger O, Mandrekar S, DeMichele A, et al: AFT-38 PATINA: A randomized, open label, phase III trial to evaluate the efficacy and safety of palbociclib + anti-HER2 therapy + endocrine therapy vs anti-HER2 therapy + endocrine therapy after induction treatment for hormone receptor–positive/HER2-positive metastatic breast cancer. 2024 San Antonio Breast Cancer Symposium. Abstract P2-03-20. Presented December 10, 2024.
- Hwang ES: Early oncologic outcomes following active monitoring or surgery (± radiation) for low risk DCIS: The Comparing an Operation to Monitoring, with or without Endocrine Therapy (COMET) study (AFT-25). 2024 San Antonio Breast Cancer Symposium. Abstract GS2-05. Presented December 12, 2024.
- Jhaveri K: Imlunestrant, an oral selective estrogen receptor degrader, as monotherapy and combined with abemaciclib, for patients with ER+ HER2– advanced breast cancer, pretreated with endocrine therapy: Results of the phase 3 EMBER-3 trial. 2024 San Antonio Breast Cancer Symposium. Abstract GS01-1. Presented December 11, 2024.
- Jhaveri KL, Neven P, Casalnuovo ML, et al: Imlunestrant with or without abemaciclib in advanced breast cancer. N Engl J Med. December 11, 2024 (early release online).
- Reimer T: No axillary surgery versus axillary sentinel lymph node biopsy in patients with early invasive breast cancer and breast-conserving surgery: Final primary results of the Intergroup-Sentinel-Mamma (INSEMA) trial. 2024 San Antonio Breast Cancer Symposium. Abstract GS2-07. Presented December 12, 2024.
- Loibl S: Primary results of the randomised phase III trial comparing first-line ET plus palbociclib vs standard mono-chemotherapy in women with high risk HER2–/HR+ metastatic breast cancer and indication for chemotherapy: PADMA study. 2024 San Antonio Breast Cancer Symposium. Abstract LB1-03. Presented December 11, 2024.
- Turner N: Circulating tumor DNA surveillance in ZEST, a randomized, phase 3, double-blind study of niraparib or placebo in patients with triple-negative breast cancer or HER2+ BRCA-mutated breast cancer with molecular residual disease after definitive therapy. 2024 San Antonio Breast Cancer Symposium. Abstract GS3-01. Presented December 13, 2024.
- Meattini I: Exclusive endocrine therapy or radiation therapy in women aged 70+ years with luminal-like early breast cancer (EUROPA): Preplanned interim analysis of of a randomized phase 3 trial. 2024 San Antonio Breast Cancer Symposium. Abstract GS2-01. Presented December 12, 2024.
